The present invention relates to a method for industrially producing 2-cyanoimino-1,3-thiazolidine useful as an intermediate material of pharmaceuticals or agrochemicals. More specifically, it relates to a method for producing a high purity 2-cyanoimino-1,3-thiazolidine using a high purity, stable intermediate N-cyanocarbonimidic acid ester, which is obtained from an alkali metal cyanide compound, an alkali metal hydroxide, a lower alcohol, chlorine and cyanamide.
Several methods have been known for the production of an N-cyanocarbonimidic acid ester. For example, 1) European Patent Publication EP14,064 (A2) (1980), Japanese Unexamined Patent Publication (Kokai) No. 5-186412 (1993), and Japanese Unexamined Patent Publication (Kokai) No. 5-186413 (1993) propose a method for obtaining N-cyanocarbonimidic acid methyl ester from sodium hydroxide and methanol and gaseous state or liquid state chlorocyan/cyanogen chloride and cyanamide. This reaction is believed to be expressed by the following formula: 
Further, 2) German Patent Publication DE3,225,249 (A1) (1983) proposes a method for obtaining N-cyanocarbonimidic acid methyl ester from sodium cyanide, sodium hydroxide, methanol, chlorine and cyanamide as shown in the following formula: 
On the other hand, 3) as a method for producing 2-cyanoimino-1,3-thiazolidine, the method of using N-cyanocarbonimidodithioic acid ester is described in Arch. Pharm. (Weiheim, Ger.), 305 (10), P731 (1972), Japanese Unexamined Patent Publication (Kokai) No. 48-91064, Gazz. Chim. Ital., 110 (506), P345, WO 92-17462 (1992), etc. This reaction is believed to be expressed by the following formula: 
Further, 4) as a method using similar starting materials, there is the disclosure in Japanese Unexamined Patent Publication (Kokai) No. 60-28969 (1985). This reaction is believed to be expressed by the following formula: 
Further, 5) regarding the method of using an N-cyanocarbonimidic acid ester, J. Heterocycl. Chem., 24 (1), P275 (1987) describes a method of using a diphenyl ester. This reaction formula is as follows: 
Further, 6) the method of using N-cyanocarbonimidic acid methyl ester is described in Org. Prep. Proced. Int., 26 (6), P721 (1991), German Patent DE4427539 (A1) (1996), and European Patent EP695744 (A1) (1996). This reaction formula is as follows: 
However, in the first proposal of using chlorocyan/cyanogen chloride, it is necessary to handle strongly poisonous chlorocyan/cyanogen chloride starting material as a gas. Special care have to be taken over the material and air-tightness of the system and the treatment facilities for the exhaust, drainage, etc., and therefore the use of this method on an industrial scale was difficult.
Further, also in the second proposal, a stable yield of the formed N-cyanocarbonimidic acid methyl ester could not be expected. Depending on the situation, the yield sometimes extremely decreased. Quality-wise as well, not only the purity is low, but also the stability becomes poor, and furthermore the hygroscopicity is strong and long term storage is not possible, and therefore it is difficult and uneconomical to use this method on an industrial scale.
Further, many N-cyanocarbonimidic acid esters are high in solubility in organic solvents. Accordingly, when concentrating and precipitating a solution containing the same to obtain crystals, the stability is poor and, therefore, the loss in the concentration stage is large and the yield becomes poor. Further, since due to the properties thereof, many esters easily hydrolyze, care is required in the temperature at the time of extraction or separation of liquid. Thus there has been a demand for simply separating and drying the products so as to obtain stable products.
Further, in particular, when methylene chloride is used among the organic solvents, since the boiling point of the methylene chloride is low, there are the problems that the yield is usually only about 50% and the cost of the starting materials becomes high. To raise the yield, special equipment such as a coolant recirculating system becomes necessary and therefore new capital investment is required.
On the other hand, in the third and fourth proposals using another compound, that is, N-cyanocarbonimidodithioic acid ester, as the starting material for the 2-cyanoimino-1,3-thiazolidine, the toxicity or inflammability or odor of the gaseous methyl mercaptan dissociating at the time of the reaction becomes a problem. Further, in the preparation of the compound, there is the problem that carbon disulfide having an extremely high inflammability or toxicity has to be used.
In the case of an N-cyanocarbonimidic acid ester, there are the effects that, since phenol or alcohol is produced as a byproduct, it is easily to recover and recycle and simultaneously the problem of toxicity or odor is eliminated. In the fifth proposal, the diphenoxy compound used is high in the price thereof and difficult to acquire. In the sixth proposal, the purity of the formed 2-cyanoimino-1,3-thiazolidine is low and regardless of the method of production, inherently requiring careful control, the settings of the conditions were insufficient and an industrially stable supply of products was difficult.
Accordingly, the object of the present invention is to solve the above problems in the prior art and to develop a method for safely industrially producing, inexpensive N-cyanocarbonimidic acid ester and 2-cyanoimino-1,3-thiazolidine.
Another object of the present invention is to provide a method for producing an N-cyanocarbonimidic acid ester and 2-cyanoimino-1,3-thiazolidine, as a high quality crystal, with a good yield and high purity.
In accordance with the present invention, it is possible to produce a high purity, stable N-cyanocarbonimidic acid ester by reacting an alkali metal cyanide compound, an alkali metal hydroxide, a lower alcohol and chlorine in an aqueous solution to form an carbonimidic acid ester solution, then adding an organic solvent thereto, followed by adding a cyanamide solution to form an N-cyanocarbonimidic acid ester, and further extracting the resultant ester with an organic solvent extracting solution, followed by washing with an aqueous solution of a reducing agent.
In accordance with the present invention, it is possible to produce high purity 2-cyanoimino-1,3-thiazolidine by reacting the high purity, stable N-cyanocarbonimidic acid ester obtained in the above method with 2-aminoethanethiol to be cyclized, in particular, without complicated purification.